(WFRF:(Harbst Katja)) conttype:(refereed) srt2:(2020-2024)
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Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer
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- Kaminska, Kamila (author)
- Lund University,Lunds universitet,Molekylära behandlingsstrategier vid bröstcancer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Melanom,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Molecular therapeutics in breast cancer,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Melanoma,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Akrap, Nina (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Molekylära behandlingsstrategier vid bröstcancer,Forskargrupper vid Lunds universitet,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Molecular therapeutics in breast cancer,Lund University Research Groups
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- Staaf, Johan (author)
- Lund University,Lunds universitet,Forskningsgrupp Lungcancer,Forskargrupper vid Lunds universitet,Bröst/lungcancer,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Research Group Lung Cancer,Lund University Research Groups,Breast/lungcancer,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- (creator_code:org_t)
- 2021-02-18
- 2021
- English.
- In: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 23:1, s. 26-26
- Journal article (peer-reviewed)
Abstract
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- BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself.METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant.RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival.CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
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- Kaminska, Kamila
- Akrap, Nina
- Staaf, Johan
- Alves, Carla L
- Ehinger, Anna
- Ebbesson, Anna
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- Veerla, Srinivas
- Harbst, Katja
- Ehmsen, Sidse
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